tbuckley/cabot-search huggingface dataset:
PATH-16. Noninvasive diagnosis of gliomas through CSF cfDNA sequencing in pediatric and adolescent and young adult (AYA) patients
Authors: Katherine Hill, Alexandra M Miller, Bryan Kincheon Li, Nancy Bouvier, Shanita Li, Tina Alano, Seyram Doe-Tetteh, Claudia Huereca, Sara DiNapoli, Alex Lee, Luca Szalontay, Cecile Riviere-Cazaux, Terry C Burns, Sofia Haque, Tejus Bale, Jamal Benhamida, Snjezana Dogan, Chad Vanderbilt, Dara Ross, Jason Chang, Maria Donzelli, Ira J Dunkel, Sameer Farouk Sait, Yasmin Khakoo, Stephen Gilheeney, Mark Souweidane, Jeffrey Greenfield, Michael Berger, Ryma Benayed, Maria E Arcila, Marc Ladanyi, Ingo Mellinghoff, Matthias Karajannis
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: A subset of pediatric, adolescent and young adult (AYA) gliomas are located in the brainstem, eloquent locations, or present with diffuse/leptomeningeal disease, and are associated with high risk and low yield of biopsy. At the same time, accurate molecular diagnosis is necessary to direct optimal therapy. In such cases, analysis of cell free DNA (cfDNA) form cerebral spinal fluid (CSF) may represent a diagnostic alternative to biopsy. METHODS: We investigated the utility of CSF cfDNA sequencing through a stepwise approach, using clinically validated, targeted molecular assays. Testing was performed using a broad hybrid capture next generation sequencing assay (MSK-IMPACT) and subsequent targeted digital droplet PCR in a subset of cases. RESULTS: We analyzed 17 CSF samples from 17 pediatric (n=6) and AYA (n=11) glioma patients with primary or recurrent disease. Thirteen had tumors located within the brainstem, and four had leptomeningeal involvement. Somatic alterations were detected in 12/17 samples (71%). In 3/4 patients with leptomeningeal involvement, cfDNA testing revealed a BRAF fusion consistent with the diagnosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). Among the 13 patients with brainstem involvement, four had somatic H3 K27M mutations, three had IDH mutations, and one had TP53 and ATRX mutations; five patients had no detectable mutations. CONCLUSION: In our analysis, we found that established glioma hotspot mutations were able to be detected within the CSF. We propose that in patients for whom tissue biopsy is high risk, not feasible, or tissue was nondiagnostic, CSF cfDNA sequencing has a substantial diagnostic yield and should be considered as a valuable novel diagnostic tool. Ongoing research is aiming to further increase the sensitivity of cfDNA testing, especially in patients with very low levels of CSF cfDNA.
Predictive factors of toxicity of immune checkpoint inhibitors (ICI) in older patients with lung cancer: The ToxImmune study.
Authors: Carole Helissey, Francoise Difoum, Hélène Vanquaethem, Perrine Vuagnat, Hugo Picchi, Audrey Le Roy, Antoine Schernberg
Journal: Journal of Clinical Oncology (2022)

12048 Background: Immunotherapy (Im) improved the survival of patients with lung cancer. It may be responsible for adverse events impacting these patients' quality of life. We have few data on the tolerance of older cancer patients (OP) to immunotherapy. The Toximmune study aims to describe the safety of older lung cancer patients to Im and identify clinical, biological and radiological markers that can help to predict immune-related adverse events for OP. Methods: All patients aged 60 years and older who had received at least one dose of ICI between June 2015 and December 2020 and diagnosed with lung cancer were included. We collected patients' baseline demographic characteristics, biological blood markers and imaging by PET-scanner. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (CTCAE V.5.0). Results: 49 patients were included, median age was 71 (range 61-97). The incidence of grade 2 and grade 3-4 was 34% and 6% respectively. The main irAEs reported were: asthenia in 51% patients after 13.5 months median delay (grade ≥2 in 22%),musculoskeletal disorders in 45% after 21 months median delay (grade ≥2 in 10%), pneumonitis in 37% after 21 months median delay (grade ≥2 in 10%), and colitis in 35% after 21 months median delay (grade ≥2 in 6%). Female sex, primitive tumor SUV max &lt; 5, number of metastases ≥ 3, prior systemic therapy &gt; 1, PLR &lt; 250 were significantly associated with a risk of toxicity in univariate analysis (p &lt; 0.05) We developed the ToxImmune score (0, 1, or ≥2) to predict the risk of having a grade ≥2 adverse event by adding the following risk factors: Primitive Tumor SUV &lt; 5 = 1, Number of metastases ≥3 = 1, And L1 = 0 vs &gt; L1 = 1. The incidence of grade ≥2 adverse events was 31%, 35% and 86% with ToxImmune scores 0, 1 and 2 respectively (p = 0.032). Median overall survival times (OS) &amp; progression-free survival (PFS) were 21.8 &amp; 21 months, 15.1 &amp; 6.6 months, and 9.8 &amp; 2.1 months for ToxImmune scores 0, 1 and ≥ 2 respectively (p = 0.06 &amp; p = 0.001). There was significant association between the ToxImmune score and the risk of "progressive disease" at the first assessment of the disease: 16% for score = 0, 48% for score = 1, and 71% for score = 2, (p = 0.01). Conclusions: The quality of life is our goal for OP care. The ToxImmune score, which is based on objective clinical parameters, identifies OP with a significant higher risk of severe adverse events. Also, this score was significantly associated with patients’ PFS risk of developing rapid tumor progression. It could be used in clinical practice to personalize toxicity surveillance in OP treated for lung cancer with immunotherapy. This score will be validated in larger prospective cohorts.
A needs assessment survey to inform a general practitioner in oncology (GPO) training program in Nepal.
Authors: Bishal Gyawali, Laura M. Carson, Niresh Thapa, Colleen Savage, Mangal Rawal, Scott R. Berry, Bishesh Sharma Poudyal
Journal: Journal of Clinical Oncology (2022)

11024 Background: Nepal is a low-income country with a population of over 30 million that faces a significant burden of cancer, with approximately 60,000 patients receiving a cancer diagnosis per year. However, a lack of cancer care providers is recognized as a major barrier to cancer care in Nepal. To address this gap, a national GPO training program may be an effective task-shifting strategy to increase the oncology workforce. A needs assessment survey was conducted to determine baseline oncology training for Nepalese General Practitioners (GPs) and the feasibility and desirability of establishing a GPO training program in Nepal. Methods: A survey was distributed to 171 GPs in Nepal. The survey was distributed via the REDCap electronic database, a secure-web-based software platform based at Queen’s University in Kingston, Ontario, Canada. Reminders were sent out via social media accounts. The survey results were recorded anonymously from February to July 2021. Results: Data was collected from 71 GPs in Nepal. Data revealed significant gaps in oncology training, with only 6% of respondents reporting undergoing a mandatory oncology rotation during their training, and 15% indicating their training adequately prepared them to care for patients with cancer. Although respondents reported seeing an average of 1-5 cancer patients per day, only 9% reported providing chemotherapy treatment, and 36% indicated regular provision of follow-up cancer care. Only 1 in 5 general practitioners reported having radiation oncology services available at their institution or an institution within the same zone. 96% of GPs surveyed agreed that there is a need for a GPO program, and 71% reported they would be very interested in participating in this type of training. A majority of respondents indicated a preference for self-directed and small-group learning as the preferred modes of content delivery in a GPO training program. Conclusions: Our findings indicate a need and high level of desirability for a national GPO training program in Nepal. Further, the needs assessment provides insight into practitioner perspectives on information needs and content delivery. This data will be used to guide future curriculum development for the Nepal GPO program. [Table: see text]
Paracrine signal emanating from stressed cardiomyocytes aggravates inflammatory microenvironment in diabetic cardiomyopathy
Authors: N Kaur, A Ruiz, R Raja, G Howell, K Mace, P Binder, C Smith, E Swanton, X Wang, J Chernoff, EJ Cartwright, W Liu
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Cardiovascular issues associated with diabetes, such as diabetic cardiomyopathy (DCM), can lead to heart failure. DCM is etiologically related to myocardial inflammation and can stem from a complex interplay of different cell types. Cardiomyocyte as an active mediator of the inflammatory response is an emerging concept with limited mechanistic understanding. Purpose We aimed to address the knowledge gap of cardiomyocyte endoplasmic reticulum (ER) dysfunction-mediated macrophage response and provide functional evidence for the therapeutic feasibility of managing inflammatory paracrine signals in response to diet-induced metabolic stress. Methods In vivo mouse model of high fat high sucrose diet-induced diabetes, cardiomyocyte-specific p21-activated kinase 2 (PAK2) knockout model, echocardiography, histology, 3D imaging, qPCR, co-culture of H9c2 culturing medium and bone-marrow derived macrophages, immunoblotting, macrophage isolation from myocardium, flow cytometry and AAV9-gene therapy. Results In a time-course study, diet-induced diabetic mice demonstrated an association between cardiac ER stress and sustained myocardial inflammation, with a maladaptive shift in myocardial ER stress response over time. Furthermore, as a cardiac ER dysfunction model, mice with cardiac-specific PAK2 deletion exhibited heightened myocardial inflammatory response in diabetes. Using human and mice diabetic heart samples, we show that ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) is a novel transcriptional regulator of high mobility group box-1 (HMGB1). Cardiac stress-induced active release of HMGB1 facilitated M1 macrophage polarization, and aggravated myocardial inflammatory signatures. Therapeutically, sequestering the extracellular HMGB1 using Glycyrrhizin conferred cardioprotection through its anti-inflammatory action. Also, as functional evidence, we showed that un-mitigated cardiac ER response due to PAK2 loss under diabetes may account as a barrier for leveraging the anti-inflammatory potential of Vildagliptin. Conclusion Collectively, we introduce an ER stress-mediated cardiomyocyte-macrophage link, altering the macrophage response in the myocardium, thereby providing insight into therapeutic prospects for diabetes-associated cardiac dysfunction.
Association of Diet Quality With Longevity and Successful Aging in Israeli Adults 65 Years or Older
Authors: Abigail Goshen, Uri Goldbourt, Yael Benyamini, Tal Shimony, Lital Keinan-Boker, Yariv Gerber
Journal: JAMA Network Open (2022)

<h3>Importance</h3> To our knowledge, the role of overall diet quality in successful aging has not been conclusively demonstrated. <h3>Objective</h3> To prospectively examine the association between diet quality and longevity and successful aging in a population-based cohort of older adults. <h3>Design, Setting, and Participants</h3> Participants in "Mabat Zahav" (the Israeli National Health and Nutrition Survey of Older Adults), an older adult cohort (aged ≥65 years) consisting of a random sample of 1770 individuals, were recruited from July 2005 to December 2006 (time 1 [T1]). Survivors of T1 were again contacted and asked to participate in a second interview. From May 2017 to June 2019 (time 2 [T2]), an extensive face-to-face interview and a functional assessment were conducted in each participant's home in a subsample of 604 participants from T1, representing 72.7% of 820 surviving individuals who were able to complete interviews and assessments. <h3>Exposures</h3> A 24-hour dietary recall, assessed at T1, was used to calculate scores from the 2015 version of the Healthy Eating Index (HEI-2015) (scores range from 0 [worst diet] to 100 [best diet]). <h3>Main Outcomes and Measures</h3> Time to death, with follow-up lasting through June 2019, and successful aging. The latter, based on T2 assessment, was defined as (objectively measured) preserved physical and cognitive function and (subjective) mental well-being and favorable self-rated health. Inverse probability weighting was used in the analysis to minimize attrition bias. <h3>Results</h3> At T1, the study included 1770 participants (mean [SD] age, 74.6 [6.2] years; 943 women [53%]). On average, participants with higher HEI-2015 scores had healthier lifestyles and higher socioeconomic status at T1. During a median follow-up duration of 12.6 years (IQR, 7.6-13.2 years), 893 deaths occurred. Among the 596 T2 participants analyzed (mean [SD] age, 84.1 [4.4] years; 334 [56%] women), 242 (40%) met successful aging criteria. After adjustment for sociodemographic and lifestyle risk factors, a higher HEI-2015 score was inversely associated with mortality (hazard ratios, 0.85; 95% CI, 0.72-0.99 in the upper tertile and 0.83; 95% CI, 0.71-0.98 in the middle tertile vs the lower tertile;<i>P</i> = .04 for trend) and was positively associated with successful aging (odds ratios, 1.73; 95% CI, 1.10-2.72 in the upper tertile and 1.30; 95% CI, 0.83-2.03 in the middle tertile vs the lower tertile;<i>P</i> = .03 for trend). <h3>Conclusions and Relevance</h3> In this cohort study of older adults in Israel, improved diet quality was associated with increased longevity and successful aging in a dose-dependent manner. These data contribute to the body of literature that suggests diet quality is associated with aging in the older age group.
LithoFree: Extraction of kidney stone dust residues post-laser-lithotripsy using magnetic separation
Authors: S.P. Schwaminger, M. Wengler, S. Srinivasan, T. Amiel, M. Busse, D.R. Gonzalez, O. Vasylenko, P. Muschak, A. Miernik, M. Straub, S. Berensmeier
Journal: European Urology (2022)
Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma
Authors: Jenette Creaney, Ann-Marie Patch, Venkateswar Addala, Sophie A. Sneddon, Katia Nones, Ian M. Dick, Y. C. Gary Lee, Felicity Newell, Ebony J. Rouse, Marjan M. Naeini, Olga Kondrashova, Vanessa Lakis, Apostolos Nakas, David Waller, Annabel Sharkey, Pamela Mukhopadhyay, Stephen H. Kazakoff, Lambros T. Koufariotis, Aimee L. Davidson, Priya Ramarao-Milne, Oliver Holmes, Qinying Xu, Conrad Leonard, Scott Wood, Sean M. Grimmond, Raphael Bueno, Dean A. Fennell, John V. Pearson, Bruce W. Robinson, Nicola Waddell
Journal: Genome Medicine (2022)

Abstract Background Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials. Methods We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study. This was combined with RNA-seq analysis to characterize the tumour immune environment. Results The comprehensive genome analysis identified 12 driver genes, including new candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed SBS5/40 were dominant in 93% of samples, and defects in homologous recombination repair were infrequent in our cohort. The tumour immune environment contained high M2 macrophage infiltrate linked with MMP2 , MMP14 , TGFB1 and CCL2 expression, representing an immune suppressive environment. The expression of TGFB1 was associated with overall survival. A small subset of samples (less than 10%) had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a ‘hot’ immune environment independent of the somatic mutations. Conclusions We propose accounting for genomic and immune microenvironment status may influence therapeutic planning in the future.
Survival benefit of postoperative adjuvant chemotherapy for patients in poor-differentiated early-stage cervical cancer: A multicenter, cohort study.
Authors: Huaiwu Lu, Miaochun Xu, Ying Zhou, Bingbing Zhao, Fang Ren, Luwei Wei, Qing Chen, Bingzhong Zhang, Zhongqiu Lin
Journal: Journal of Clinical Oncology (2022)

e17509 Background: Postoperative adjuvant therapy decisions for early-stage cervical cancer (ESCC) without high risk factor, including parametrial extension, positive nodes and positive margins, now depend on Sedlis criteria, which do not mention the degree of differentiation. In this study, we aimed to explore the benefit of adjuvant chemotherapy for patients of ESCC with poor differentiation but without positive Sedlis criteria after radical hysterectomy, and develop a score to predict the recurrence risk in these patients, so as to further improve the indications of postoperative adjuvant therapy for patients of ESCC. Methods: Patients of ESCC with pathologically proven poor differentiation after radical hysterectomy were prospectively included in a multicenter study. Univariate Cox proportional hazards regression were developed to evaluate the independent risk factors for recurrence. The log-rank test was performed to compare the progression-free survival (PFS) and overall survival (OS) of adjuvant chemotherapy (ACT) and no further treatment (NFT) groups. Selected variables were analyzed in a Multivariate Cox Regression Model and used to build a nomogram for ESCC to predict the survival probabilities. Results: In total, 352 patients were randomly assigned to two groups, a training group and a validation group, at a ratio of 1:1 (176 patients: 176 patients). In both of training and validation cohort, the ACT groups had longer PFS than the NFT groups ( P= 0.007 and 0.016, respectively), while the differences of OS were not statistically significant ( P= 0.922 and 0.107, respectively). In the multivariate analysis, ACT was proved an independent prognostic factor for the PFS (P = 0.048), and the strongest predictor of PFS even analyzing with other potential independent prognostic factors (HR 0.116, 95%CI 0.014-0.981). Five factors, including postoperative treatment, histologic type, isthmus uteri involvement, FIGO stage, SCCA level, were included in the nomogram to predict survival probabilities in the training cohort and performed well in the validation cohorts. Conclusions: For the patients of ESCC who don't meet to Sedlis criteria but with poor differentiation, ACT after radical hysterectomy can reduce the recurrence rate.
COVID-19 Cases, Hospitalizations, and Deaths Among American Indian or Alaska Native Persons — Alaska, 2020–2021
Authors: Lowrie A. Ward, Kelsey P. Black, Carla L. Britton, Megan L. Tompkins, Ellen M. Provost
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

American Indian or Alaska Native (AI/AN) persons across the United States face substantial health disparities, including a disproportionately higher incidence of COVID-19 (1,2). AI/AN persons living in Alaska also face serious health and health care challenges, including access to care because 90% of the state's land area is inaccessible by road (3), and approximately one half of the state's AI/AN population (AI/AN race alone or in combination with another race) live in remote rural areas (4). To examine the extent of COVID-19-associated disparities among AI/AN persons living in Alaska, a retrospective analysis of COVID-19 cases reported to the Alaska Department of Health and Social Services (AKDHSS) during March 12, 2020-December 31, 2021, was conducted. The age-adjusted COVID-19 incidence among AI/AN persons was 26,583 per 100,000 standard population, approximately twice the rate among White persons living in Alaska (11,935). The age-adjusted COVID-19-associated hospitalization rate among AI/AN persons was 742 per 100,000, nearly three times the rate among White persons (273) (rate ratio [RR] = 2.72). The age-adjusted COVID-19-related mortality rate among AI/AN persons was 297 per 100,000, approximately three times that among White persons (104; RR = 2.86). Culturally competent public health efforts that are designed in collaboration with AI/AN persons and communities, including support for vaccination and other proven COVID-19 prevention strategies, are critical to reducing COVID-19-associated disparities among AI/AN persons in Alaska.
Association of <i>TP53</i> polymorphisms with the acquisition of <i>EGFR</i> T790M mutations in patients with first- or second-generation EGFR-TIK progression.
Authors: Huajie Dong, Tong Zhou, Peng Li, Changling Wu, Hongjun Lu, Lele Zhao, Xueyu Yang, Wanglong Deng, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e20560 Background: Lung cancer is the leading cause of cancer death worldwide. EGFR tyrosine kinase inhibitors (TKIs) has transformed management in those patients. However, the majority of patients will become resistant to EGFR-TKIs after a period of time. The T790M acquired mutation in exon 20 of the EGFR is the predominant molecular mechanism of acquired resistance. In first-line treatment of global patients with NSCLC, osimertinib had better efficacy compared to first-generation TKIs. In the FLAURA study, the median PFS with first-line osimertinib in Asians was only 16.5 months, compared to 18.6 months in the global population. Moreover, the OS benefit in the Asian population was relatively small. At the same time, the mechanism of resistance to osimertinib is very complex and patients have limited treatment options after first-line osimertinib resistance. A variety of factors can influence the decision for first-line treatment in EGFR mutation-positive patients, including follow-up regimens, the presence of brain metastases, and tolerability, all of which should be considered in the long-term treatment plan. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions. Previous studies have shown that TP53 Arg72Pro polymorphism (rs1042522) is associated with the risk and prognosis of lung cancer. Currently, the association between EGFR mutations and TP53 polymorphisms is unclear, but previous reports have suggested that patients with EGFRmutation demonstrated a higher rate of TP53 mutation than EGFR wild type patients. Therefore, this study aim to explore the association of TP53 polymorphisms (rs1042522) with EGFR T790M acquired mutations, considering the value of T790M in lung cancer treatment. Methods: We analyzed two independent cohorts of patients with EGFR-mutant NSCLC who progressed after first-line EGFR-TKIs treatment from 2013 to 2021 (cohort 1: n=108; cohort 2: n=148). All patients were tested with plasma next-generation sequencing (NGS). Results: The acquired T790M mutation rate was 36%, 30% and 43% in all patients (n = 256), cohort 1 and cohort 2, respectively. Logistic regression analysis showed that TP53 rs1042522 polymorphism was significantly associated with an increased risk of T790M acquired mutation in cohort 1 (GG versus CC: OR (95% CI) = 3.57 (1.15-12.2), P = 0.033) and cohort 2 (GG versus CC: univariable OR (95% CI) = 3.53 (1.30-10.3), P = 0.016; multivariable OR (95% CI) = 2.94 (1.04-8.87), P= 0.047). Conclusions: We found that the TP53 rs1042522 polymorphism GG was associated with EGFR T790M acquired mutations. Knowing in advance whether patients are likely to acquire EGFR T790M mutations will help in making treatment decisions.